The present invention relates to piperazine derivatives useful as selective CCR5 antagonists, pharmaceutical compositions containing the compounds, and methods of treatment using the compounds. The invention also relates to the use of a combination of a CCR5 antagonist of this invention and one or more antiviral or other agents useful in the treatment of Human Immunodeficiency Virus (HIV). The invention further relates to the use of a CCR-5 antagonist of this invention, alone or in combination with another agent, in the treatment of solid organ transplant rejection, graft v. host disease, arthritis, rheumatoid arthritis, inflammatory bowel disease, atopic dermatitis, psoriasis, asthma, allergies or multiple sclerosis.
The global health crisis caused by HIV, the causative agent of Acquired Immunodeficiency Syndrome (AIDS), is unquestioned, and while recent advances in drug therapies have been successful in slowing the progression of AIDS, there is still a need to find a safer, more efficient, less expensive way to control the virus.
It has been reported that the CCR5 gene plays a role in resistance to HIV infection. HIV infection begins by attachment of the virus to a target cell membrane through interaction with the cellular receptor CD4 and a secondary chemokine co-receptor molecule, and proceeds by replication and dissemination of infected cells through the blood and other tissue. There are various chemokine receptors, but for macrophage-tropic HIV, believed to be the key pathogenic strain that replicates in vivo in the early stages of infection, the principal chemokine receptor required for the entry of HIV into the cell is CCR5. Therefore, interfering with the interaction between the viral receptor CCR5 and HIV can block HIV entry into the cell. The present invention relates to small molecules which are CCR5 antagonists.
CCR-5 receptors have been reported to mediate cell transfer in inflammatory diseases such as arthritis, rheumatoid arthritis, atopic dermatitis, psoriasis, asthma and allergies, and inhibitors of such receptors are expected to be useful in the treatment of such diseases, and in the treatment of other inflammatory diseases or conditions such as inflammatory bowel disease, multiple sclerosis, solid organ transplant rejection and graft v. host disease.
Related piperazine derivatives which are muscarinic antagonists useful in the treatment of cognitive disorders such as Alzheimer""s disease are disclosed in U.S. Pat. Nos 5,883,096; 6,037,352; 5,889,006.
A-M. Vandamme et al., Antiviral Chemistry and Chemotherapy, 9:187-203 (1998) disclose current clinical treatments of HIV-1 infections in man including at least triple drug combinations or so-called Highly Active Antiretroviral Therapy (xe2x80x9cHAARTxe2x80x9d); HAART involves various combinations of nucleoside reverse transcriptase inhibitors (xe2x80x9cNRTIxe2x80x9d), non-nucleoside reverse transcriptase inhibitors (xe2x80x9cNNRTIxe2x80x9d) and HIV protease inhibitors (xe2x80x9cPIxe2x80x9d). In compliant drug-naive patients, HAART is effective in reducing mortality and progression of HIV-1 to AIDS. However, these multidrug therapies do not eliminate HIV-1 and long-term treatment usually results in multidrug resistance. Development of new drug therapies to provide better HIV-1 treatment remains a priority.
The present invention relates to the treatment of HIV comprising administering to a mammal in need of such treatment an effective amount of a CCR5 antagonist represented by the structural formula I: 
or a pharmaceutically acceptable salt thereof, wherein
R is R8-phenyl, R8-pyridyl, R8-thiophenyl or R8-naphthyl;
R1 is hydrogen or C1-C6 alkyl;
R2 is R9, R10, R11-phenyl; R9, R10, R11-substituted 6-membered heteroaryl; R9, R10, R11-substituted 6-membered heteroaryl N-oxide; R12, R13-substituted 5-membered heteroaryl; naphthyl; fluorenyl; diphenylmethyl 
R3 is hydrogen, C1-C6 alkyl, (C1-C6)alkoxy(C1-C6)alkyl, C3-C10 cycloalkyl, C3-C10 cycloalkyl(C1-C6)alkyl, R8-phenyl, R8-phenyl(C1-C6)alkyl, R8-naphthyl, R8-naphthyl(C1-C6)alkyl, R8-heteroaryl or R8-heteroaryl(C1-C6)alkyl;
R4, R5, R7 and R13 are independently selected from the group consisting of hydrogen and (C1-C6)-alkyl;
R6 is hydrogen, C1-C6 alkyl or C2-C6 alkenyl;
R8 is 1 to 3 substituents independently selected from the group consisting of hydrogen, halogen, C1-C6 alkyl, C1-C6 alkoxy, xe2x80x94CF3, CF3Oxe2x80x94, CH3C(O)xe2x80x94, xe2x80x94CN, CH3SO2xe2x80x94, CF3SO2xe2x80x94, R14-phenyl, R14-benzyl, CH3C(xe2x95x90NOCH3), CH3C(xe2x95x90NOCH2CH3), 
xe2x80x83xe2x80x94NH2, xe2x80x94NHCOCF3, xe2x80x94NHCONH(C1-C6 alkyl), xe2x80x94NHCO(C1-C6 alkyl), xe2x80x94NHSO2(C1-C6 alkyl), 5-membered heteroaryl and 
xe2x80x83wherein X is xe2x80x94Oxe2x80x94, xe2x80x94NHxe2x80x94 or xe2x80x94N(CH3)xe2x80x94;
R9 and R10 are independently selected from the group consisting of (C1-C6)alkyl, halogen, xe2x80x94NR17R18, xe2x80x94OH, xe2x80x94CF3, xe2x80x94OCH3, xe2x80x94O-acyl, xe2x80x94OCF3 and xe2x80x94Si(CH3)3;
R11 is R9, hydrogen, phenyl, xe2x80x94NO2, xe2x80x94CN, xe2x80x94CH2F, xe2x80x94CHF2, xe2x80x94CHO, xe2x80x94CHxe2x95x90NOR17, pyridyl, pyridyl N-oxide, pyrimidinyl, pyrazinyl, xe2x80x94N(R17)CONR18R19, xe2x80x94NHCONH(chloro-(C1-C6)alkyl), xe2x80x94NHCONH((C3-C1)cycloalkyl(C1-C6)alkyl), xe2x80x94NHCO(C1-C6)alkyl, xe2x80x94NHCOCF3, xe2x80x94NHSO2N((C1-C6)alkyl)2, xe2x80x94NHSO2(C1-C6)alkyl, xe2x80x94N(SO2CF3)2, xe2x80x94NHCO2(C1-C6)alkyl, C3-C10 cycloalkyl, xe2x80x94SR20, xe2x80x94SOR20, xe2x80x94SO2R20, xe2x80x94SO2NH(C1-C6 alkyl), xe2x80x94OSO2(C1-C6)alkyl, xe2x80x94OSO2CF3, hydroxy(C1-C6)alkyl, xe2x80x94CON R17R18, xe2x80x94CON(CH2CH2xe2x80x94Oxe2x80x94 CH3)2, xe2x80x94OCONH(C1-C6)alkyl, xe2x80x94CO2R17, xe2x80x94Si(CH3)3 or xe2x80x94B(OC(CH3)2)
R12 is (C1-C6)alkyl, xe2x80x94NH2 or R14-phenyl;
R14 is 1 to 3 substituents independently selected from the group consisting of hydrogen, (C1-C6) alkyl, xe2x80x94CF3, xe2x80x94CO2R17, xe2x80x94CN, (C1-C6)alkoxy and halogen;
R15 and R16 are independently selected from the group consisting of hydrogen and C1-C6 alkyl, or R15 and R16 together are a C2-C5 alkylene group and with the carbon to which they are attached form a Spiro ring of 3 to 6 carbon atoms;
R17, R18 and R19 are independently selected from the group consisting of H and C1-C6 alkyl; and
R20 is C1-C6 alkyl or phenyl.
Preferred are compounds of formula I wherein R is R8-phenyl or R8-naphthyl, especially wherein R8 is a single substituent, and especially wherein the R8 substituent is in the 4-position. For R8-phenyl, preferred R8 substituents are xe2x80x94CF3, xe2x80x94OCF3, CH3SO2xe2x80x94, CH3COxe2x80x94, CH3C(xe2x95x90NOCH3)xe2x80x94, Br and I. For R8-naphthyl, R8 is preferably C1-C6 alkoxy. Also preferred are compounds of formula I wherein R3 is hydrogen, (C1-C6) alkyl, R8-phenyl. R8-benzyl or R8-pyridyl; more preferred definitions for R3 are methyl, ethyl, phenyl, benzyl and pyridyl. R1 is preferably hydrogen. For compounds of formula 1, R6 is preferably hydrogen or methyl, especially methyl. R4 is preferably methyl; R5 and R7 are each preferably hydrogen.
In compounds of formula 1, R2 is preferably R9, R10, R11-phenyl, R9, R10, R11-pyridyl or an N-oxide thereof, or R9, R10, R11-pyrimidyl. When R2 is pyridyl, it is preferably 3- or 4-pyridyl, and when pyrimidyl, it is preferably 5-pyrimidyl. The R9 and R10 substituents are preferably attached to carbon ring members adjacent to the carbon joining the ring to the rest of the molecule and the R11 substituent can be attached to any of the remaining unsubstituted carbon ring members, for example as shown in the following structures: 
Preferred R9 and R10 substituents are: (C1-C6)alkyl, especially methyl; halogen, especially chloro or bromo, xe2x80x94OH and xe2x80x94NH2. When R2 is phenyl, R11 is preferably hydrogen or xe2x80x94OH; when R2 is pyridyl, R11 is preferably hydrogen; and when R2 is pyrimidyl, R11 is preferably hydrogen, methyl or phenyl. Examples of particularly preferred R2 groups are as follows: 
Also claimed are novel CCR5 antagonist compounds represented by the structural formula II 
or a pharmaceutically acceptable salt thereof, wherein
(1) Ra is R8a-phenyl, R8b-pyridyl, R8b-thiophenyl or R8-naphthyl;
R1 is hydrogen or C1-C6 alkyl;
R2 is R9, R10, R11-phenyl; R9, R10, R11-substituted 6-membered heteroaryl; R9, R10, R11-substituted 6-membered heteroaryl N-oxide; R12, R13-substituted 5-membered heteroaryl; naphthyl; fluorenyl; diphenylmethyl, 
R3 is hydrogen, C1-C6 alkyl, (C1-C6)alkoxy(C1-C6)alkyl, C3-C10 cycloalkyl, C3-C10 cycloalkyl(C1-C6)alkyl, R8-phenyl, R8-phenyl(C1-C6)alkyl, R8-naphthyl, R8-naphthyl(C1-C6)alkyl, R8-heteroaryl or R8-heteroaryl(C1-C6)alkyl;
R4, R5, R7 and R13 are independently selected from the group consisting of hydrogen and (C1-C6)-alkyl;
R6 is hydrogen, C1-C6 alkyl or C2-C6 alkenyl;
R8 is 1 to 3 substituents independently selected from the group consisting of hydrogen, halogen, C1-C6 alkyl, C1-C6 alkoxy, xe2x80x94CF3, CF3Oxe2x80x94, CH3C(O)xe2x80x94, xe2x80x94CN, CH3SO2xe2x80x94, CF3SO2xe2x80x94, R14-phenyl, R14-benzyl, CH3C(xe2x95x90NOCH3), CH3C(xe2x95x90NOCH2CH3), 
xe2x80x83xe2x80x94NH2, xe2x80x94NHCOCF3, xe2x80x94NHCONH(C1-C6 alkyl), xe2x80x94NHCO(C1-C6 alkyl), xe2x80x94NHSO2(C1-C6 alkyl), 5-membered heteroaryl and 
xe2x80x83wherein X is xe2x80x94Oxe2x80x94, xe2x80x94NHxe2x80x94 or xe2x80x94N(CH3)xe2x80x94;
R8a is 1 to 3 substituents independently selected from the group consisting of hydrogen, halogen, xe2x80x94CF3, CF3Oxe2x80x94, xe2x80x94CN, CF3SO2xe2x80x94, R14-phenyl, xe2x80x94NHCOCF3, 5-membered heteroaryl and 
xe2x80x83wherein X is as defined above;
R8b is 1 to 3 substituents independently selected from the group consisting of hydrogen, halogen, xe2x80x94CF3, CF3Oxe2x80x94, CH3C(O)xe2x80x94, xe2x80x94CN, CF3SO2xe2x80x94, R14-benzyl, CH3C(xe2x95x90NOCH3), CH3C(xe2x95x90NOCH2CH3), 
xe2x80x83xe2x80x94NHCOCF3, 5-membered heteroaryl and 
xe2x80x83wherein X is as defined above;
R9 and R10 are independently selected from the group consisting of (C1-C6)alkyl, halogen, xe2x80x94NR17R18, xe2x80x94OH, xe2x80x94CF3, xe2x80x94OCH3, xe2x80x94O-acyl, xe2x80x94OCF3 and xe2x80x94Si(CH3)3;
R11 is R9, hydrogen, phenyl, xe2x80x94NO2, xe2x80x94CN, xe2x80x94CH2F, xe2x80x94CHF2, xe2x80x94CHO, xe2x80x94CHxe2x95x90NOR17, pyridyl, pyridyl N-oxide, pyrimidinyl, pyrazinyl, xe2x80x94N(R17)CONR18R19, xe2x80x94NHCONH(chloro-(C1-C6)alkyl), xe2x80x94NHCONH((C3-C1)cycloalkyl(C1-C6)alkyl), xe2x80x94NHCO(C1-C6)alkyl, xe2x80x94NHCOCF3, xe2x80x94NHSO2N((C1-C6)alkyl)2, xe2x80x94NHSO2(C1-C6)alkyl, xe2x80x94N(SO2CF3)2, xe2x80x94NHCO2(C1-C6cycloalkyl, xe2x80x94SR20 , xe2x80x94SO , xe2x80x94SO2R20, xe2x80x94SO2NH(C1-C6 alkyl), xe2x80x94OSO2(C1C6)alkyl, xe2x80x94OSO2CF3, hydroxy(C1-C6)alkyl, xe2x80x94CON R17R18, xe2x80x94CON(CH2CH2xe2x80x94Oxe2x80x94CH3)2, xe2x80x94OCONH(C1-C6)alkyl, xe2x80x94CO2R17, xe2x80x94Si(CH3)3 or xe2x80x94B(OC(CH3)2)2;
R12 is (C1-C6)alkyl, xe2x80x94NH2 or R14-phenyl;
R14 is 1 to 3 substituents independently selected from the group consisting of hydrogen, (C1-C6) alkyl, xe2x80x94CF3, xe2x80x94CO2R17, xe2x80x94CN, (C1-C6)alkoxy and halogen;
R15 and R16 are independently selected from the group consisting of hydrogen and C1-C6 alkyl, or R15 and R16 together are a C2-C5 alkylene group and with the carbon to which they are attached form a Spiro ring of 3 to 6 carbon atoms;
R17, R18 and R19 are independently selected from the group consisting of H and C1-C6 alkyl; and
R20 is C1-C6 alkyl or phenyl; or
(2) Ra is R8-phenyl, R8-pyridyl or R8-thiophenyl;
R2 is fluorenyl, diphenylmethyl, 
and R1, R3, R4, R5, R6, R7, R8, R9, R10, R11, R12, R13, R14, R15, R16, R17, R18, R19 and R20 are as defined in (1).
Preferred compounds of formula II are those defined in (1).
More preferred are those of formula II(1) wherein Ra is R8a-phenyl or R8-naphthyl, wherein R8a is xe2x80x94CF3, CF3Oxe2x80x94 or halogen and R8 is C1-C6 alkoxy. The R8a or R8 substituent is preferably a single substituent; it is especially preferred that the R8a or R8 substituent is in the 4-position. Also preferred are compounds of formula II(1) wherein R3 is hydrogen, (C1-C6) alkyl, R8-phenyl. R8-benzyl or R8-pyridyl; more preferred definitions for R3 are methyl, ethyl, phenyl, benzyl and pyridyl. R1 is preferably hydrogen. For compounds of formula II(1), R6 is preferably hydrogen or methyl, especially methyl. R4 is preferably methyl; R5 and R7 are each preferably hydrogen.
R2 in formula II(1) is preferably as defined for formula 1, i.e., R9, R10, R11-phenyl, R9, R10, R11-pyridyl or an N-oxide thereof, or R9, R10, R11-pyrimidyl, wherein the R9, R10, R11-substitution is as defined above for preferred compounds of formula I.
Another aspect of the invention is a pharmaceutical composition for treatment of HIV comprising an effective amount of a CCR5 antagonist of formula If in combination with a pharmaceutically acceptable carrier. Another aspect of the invention is a pharmaceutical composition for treatment of solid organ transplant rejection, graft v. host disease, arthritis, rheumatoid arthritis, inflammatory bowel disease, atopic dermatitis, psoriasis, asthma, allergies or multiple sclerosis comprising an effective amount of a CCR5 antagonist of formula II in combination with a pharmaceutically acceptable carrier.
Yet another aspect of this invention is a method of treatment of HIV comprising administering to a human in need of such treatment an effective amount of a CCR5 antagonist compound of formula II. Another aspect of the invention is a method of treatment of solid organ transplant rejection, graft v. host disease, arthritis, rheumatoid arthritis, inflammatory bowel disease, atopic dermatitis, psoriasis, asthma, allergies or multiple sclerosis comprising administering to a human in need of such treatment an effective amount of a CCR5 antagonist compound of formula I or II.
Still another aspect of this invention is the use of a CCR5 antagonist of formula I or II of this invention in combination with one or more antiviral or other agents useful in the treatment of Human Immunodeficiency Virus for the treatment of AIDS. Still another aspect of this invention is the use of a CCR5 antagonist of formula I or II of this invention in combination with one or more other agents useful in the treatment of solid organ transplant rejection, graft v. host disease, inflammatory bowel disease, rheumatoid arthritis or multiple sclerosis. The CCR5 and antiviral or other agents which are components of the combination can be administered in a single dosage form or they can be administered separately; a kit comprising separate dosage forms of the actives is also contemplated.
As used herein, the following terms are used as defined below unless otherwise indicated.
Alkyl represents straight and branched carbon chains and contains from one to six carbon atoms.
Alkenyl represents C2-C6 carbon chains having one or two unsaturated bonds, provided that two unsaturated bonds are not adjacent to each other.
Substituted phenyl means that the phenyl group can be substituted at any available position on the phenyl ring.
Acyl means a radical of a carboxylic acid having the formula alkyl-C(O)xe2x80x94, aryl-C(O)xe2x80x94, aralkyl-C(O)xe2x80x94, (C3-C7)cycloalkyl-C(O)xe2x80x94, (C3-C7)cycloalkyl-(C1-C6)alkyl-C(O)xe2x80x94, and heteroaryl-C(O)xe2x80x94, wherein alkyl and heteroaryl are as defined herein; aryl is R14-phenyl or R14-naphthyl; and aralkyl is aryl-(C1-C6)alkyl, wherein aryl is as defined above.
Heteroaryl represents cyclic aromatic groups of 5 or 6 atoms or bicyclic groups of 11 to 12 atoms having 1 or 2 heteroatoms independently selected from O, S or N, said heteroatom(s) interrupting a carbocyclic ring structure and having a sufficient number of delocalized pi electrons to provide aromatic character, provided that the rings do not contain adjacent oxygen and/or sulfur atoms. For 6-membered heteroaryl rings, carbon atoms can be substituted by R9, R10 or R11 groups. Nitrogen atoms can form an N-oxide. All regioisomers are contemplated, e.g., 2-pyridyl, 3-pyridyl and 4-pyridyl. Typical 6-membered heteroaryl groups are pyridyl, pyrimidinyl, pyrazinyl, pyridazinyl and the N-oxides thereof. For 5-membered heteroaryl rings, carbon atoms can be substituted by R12 or R13 groups. Typical 5-membered heteroaryl rings are furyl, thienyl, pyrrolyl, thiazolyl, isothiazolyl, imidazolyl, pyrazolyl and isoxazolyl. 5-Membered rings having one heteroatom can be joined through the 2- or 3-position; 5-membered rings having two heteroatoms are preferably joined through the 4-position. Bicyclic groups typically are benzo-fused ring systems derived from the heteroaryl groups named above, e.g. quinolyl, phthalazinyl, quinazolinyl, benzofuranyl, benzothienyl and indolyl.
Preferred points of substitution for 6-membered heteroaryl rings at R2 are described above. When R2 is a 5-membered heteroaryl group, the R12 and R13 substituents are preferably attached to carbon ring members adjacent to the carbon joining the ring to the rest of the molecule, and R12 is preferably alkyl; however, if a heteroatom is adjacent to the carbon joining the ring to the rest of the molecule (i.e., as in 2-pyrrolyl), R12 is preferably attached to a carbon ring member adjacent to the carbon joining the ring to the rest of the molecule.
Halogen represents fluoro, chloro, bromo and iodo.
One or more, preferably one to four, antiviral agents useful in anti-HIV-1 therapy may be used in combination with a CCR5 antagonist of the present invention. The antiviral agent or agents may be combined with the CCR5 antagonist in a single dosage form, or the CCR5 antagonist and the antiviral agent or agents may be administered simultaneously or sequentially as separate dosage forms. The antiviral agents contemplated for use in combination with the compounds of the present invention comprise nucleoside and nucleotide reverse transcriptase inhibitors, non-nucleoside reverse transcriptase inhibitors, protease inhibitors and other antiviral drugs listed below not falling within these classifications. In particular, the combinations known as HAART (Highly Active Antiretroviral Therapy) are contemplated for use in combination with the CCR5 antagonists of this invention.
The term xe2x80x9cnucleoside and nucleotide reverse transcriptase inhibitorsxe2x80x9d (xe2x80x9cNRTIxe2x80x9d s) as used herein means nucleosides and nucleotides and analogues thereof that inhibit the activity of HIV-1 reverse transcriptase, the enzyme which catalyzes the conversion of viral genomic HIV-1 RNA into proviral HIV-1 DNA.
Typical suitable NRTIs include zidovudine (AZT) available under the RETROVIR tradename from Glaxo-Wellcome Inc., Research Triangle, NC 27709; didanosine (ddl) available under the VIDEX tradename from Bristol-Myers Squibb Co., Princeton, N.J. 08543; zalcitabine (ddC) available under the HIVID tradename from Roche Pharmaceuticals, Nutley, N.J. 07110; stavudine (d4T) available under the ZERIT trademark from Bristol-Myers Squibb Co., Princeton, N.J. 08543; lamivudine (3TC) available under the EPIVIR tradename from Glaxo-Wellcome Research Triangle, NC 27709; abacavir (1592U89) disclosed in WO96/30025 and available under the ZIAGEN trademark from Glaxo-Wellcome Research Triangle, NC 27709; adefovir dipivoxil [bis(POM)-PMEA] available under the PREVON tradename from Gilead Sciences, Foster City, Calif. 94404; lobucavir (BMS-180194), a nucleoside reverse transcriptase inhibitor disclosed in EP-0358154 and EP-0736533 and under development by Bristol-Myers Squibb, Princeton, N.J. 08543; BCH-10652, a reverse transcriptase inhibitor (in the form of a racemic mixture of BCH-10618 and BCH-10619) under development by Biochem Pharma, Laval, Quebec H7V, 4A7, Canada; emitricitabine [(xe2x88x92)-FTC] licensed from Emory University under Emory Univ. U.S. Pat. No. 5,814,639 and under development by Triangle Pharmaceuticals, Durham, N.C. 27707; beta-L-FD4 (also called beta-L-D4C and named beta-L-2xe2x80x2, 3xe2x80x2-dideoxy-5-fluoro-cytidene) licensed by Yale University to Vion Pharmaceuticals, New Haven Conn. 06511; DAPD, the purine nucleoside, (xe2x88x92)-beta-D-2,6,-diamino-purine dioxolane disclosed in EP 0656778 and licensed by Emory University and the University of Georgia to Triangle Pharmaceuticals, Durham, N.C. 27707; and lodenosine (FddA), 9-(2,3-dideoxy-2-fluoro-b-D-threo-pentofuranosyl)adenine, a acid stable purine-based reverse transcriptase inhibitor discovered by the NIH and under development by U.S. Bioscience Inc., West Conshohoken, Pa. 19428.
The term xe2x80x9cnon-nucleoside reverse transcriptase inhibitorsxe2x80x9d (xe2x80x9cNNRTIxe2x80x9ds) as used herein means non-nucleosides that inhibit the activity of HIV-1 reverse transcriptase.
Typical suitable NNRTIs include nevirapine (BI-RG-587) available under the VIRAMUNE tradename from Boehringer Ingelheim, the manufacturer for Roxane Laboratories, Columbus, Ohio 43216; delaviradine (BHAP, U-90152) available under the RESCRIPTOR tradename from Pharmacia and Upjohn Co., Bridgewater N.J. 08807; efavirenz (DMP-266) a benzoxazin-2-one disclosed in WO94/03440 and available under the SUSTIVA tradename from DuPont Pharmaceutical Co., Wilmington, Del. 19880-0723; PNU-142721, a furopyridine-thio-pyrimide under development by Pharmacia and Upjohn, Bridgewater N.J. 08807; AG-1549 (formerly Shionogi # S-1153); 5-(3,5-dichlorophenyl)-thio-4-isopropyl-1-(4-pyridyl)methyl-1H-imidazol-2-ylmethyl carbonate disclosed in WO 96 /10019 and under clinical development by Agouron Pharmaceuticals, Inc., LaJolla Calif. 92037-1020; MKC-442 (1-(ethoxy-methyl)-5-(1-methylethyl)-6-(phenylmethyl)-(2,4(1H,3H)-pyrimidinedione) discovered by Mitsubishi Chemical Co. and under development by Triangle Pharmaceuticals, Durham, N.C. 27707; and (+)-calanolide A (NSC-675451) and B, coumarin derivatives disclosed in NIH U.S. Pat. No. 5,489,697, licensed to Med Chem Research, which is co-developing (+) calanolide A with Vita-invest as an orally administrable product.
The term xe2x80x9cprotease inhibitorxe2x80x9d (xe2x80x9cPIxe2x80x9d) as used herein means inhibitors of the HIV-1 protease, an enzyme required for the proteolytic cleavage of viral polyprotein precursors (e.g., viral GAG and GAG Pol polyproteins), into the individual functional proteins found in infectious HIV-1. HIV protease inhibitors include compounds having a peptidomimetic structure, high molecular weight (7600 daltons) and substantial peptide character, e.g. CRIXIVAN(available from Merck) as well as nonpeptide protease inhibitors e.g., VIRACEPT (available from Agouron).
Typical suitable PIs include saquinavir (Ro 31-8959) available in hard gel capsules under the INVIRASE tradename and as soft gel capsules under the FORTOUASE tradename from Roche Pharmaceuticals, Nutley, N.J. 07110-1199; ritonavir (ABT-538) available under the NORVIR tradename from Abbott Laboratories, Abbott Park, Ill. 60064; indinavir (MK-639) available under the CRIXIVAN tradename from Merck and Co., Inc., West Point, Pa. 19486-0004; nelfnavir (AG-1343) available under the VIRACEPT tradename from Agouron Pharmaceuticals, Inc., LaJolla Calif. 92037-1020; amprenavir (14lW94), tradename AGENERASE, a non-peptide protease inhibitor under development by Vertex Pharmaceuticals, Inc., Cambridge, Mass. 02139-4211 and available from Glaxo-Wellcome, Research Triangle, NC under an expanded access program; lasinavir (BMS-234475) available from Bristol-Myers Squibb, Princeton, N.J. 08543 (originally discovered by Novartis, Basel, Switzerland (CGP-61755); DMP-450, a cyclic urea discovered by Dupont and under development by Triangle Pharmaceuticals; BMS-2322623, an azapeptide under development by Bristol-Myers Squibb, Princeton, N.J. 08543, as a 2nd-generation HIV-1 PI; ABT-378 under development by Abbott, Abbott Park, Ill. 60064; and AG-1549 an orally active imidazole carbamate discovered by Shionogi (Shionogi #S-1153) and under development by Agouron Pharmaceuticals, Inc., LaJolla Calif. 92037-1020.
Other antiviral agents include hydroxyurea, ribavirin, IL-2, IL-12, pentafuside and Yissum Project No. 11607. Hydroxyurea (Droxia), a ribonucleoside triphosphate reductase inhibitor, the enzyme involved in the activation of T-cells, was discovered at the NCl is under development by Bristol-Myers Squibb; in preclinical studies, it was shown to have a synergistic effect on the activity of didanosine and has been studied with stavudine. IL-2 is disclosed in Ajinomoto EP-0142268 , Takeda EP-0176299, and Chiron U.S. Pat. Nos. RE 33653, 4530787, 4569790, 4604377, 4748234, 4752585, and 4949314 is available under the PROLEUKIN (aldesleukin) tradename from Chiron Corp., Emeryville, Calif. 94608-2997 as a lyophilized powder for IV infusion or sc administration upon reconstitution and dilution with water; a dose of about 1 to about 20 million IU/day, sc is preferred; a dose of about 15 million IU/day, sc is more preferred. IL-12 is disclosed in WO96/25171 and is available from Roche Pharmaceuticals, Nutley, N.J. 07110-1199 and American Home Products, Madison, N.J. 07940; a dose of about 0.5 microgram/kg/day to about 10 microgram/kg/day, sc is preferred. Pentafuside (DP-178, T-20) a 36-amino acid synthetic peptide, disclosed in U.S. Pat. No. 5,464,933 licensed from Duke University to Trimeris which is developing pentafuside in collaboration with Duke University; pentafuside acts by inhibiting fusion of HIV-1 to target membranes. Pentafuside (3-100 mg /day) is given as a continuous sc infusion or injection together with efavirenz and 2 PI""s to HIV-1 positive patients refractory to a triple combination therapy; use of 100 mg/day is preferred. Yissum Project No. 11607, a synthetic protein based on the HIV-1 Vif protein, is under preclinical development by Yissum Research Development Co., Jerusalem 91042, Israel. Ribavirin, 1-xcex2-D-ribofuranosyl-1H-1,2,4-triazole-3-carboxamide, is available from ICN Pharmaceuticals, Inc., Costa Mesa, Calif.; its manufacture and formulation are described in U.S. Pat. No. 4,211,771.
The term xe2x80x9canti-HIV-1 therapyxe2x80x9d as used herein means any anti-HIV-1 drug found useful for treating HIV-1 infections in man alone, or as part of multidrug combination therapies, especially the HAART triple and quadruple combination therapies. Typical suitable known anti-HIV-1 therapies include, but are not limited to multidrug combination therapies such as (i) at least three anti-HIV-1 drugs selected from two NRTIs, one PI, a second PI, and one NNRTI; and (ii) at least two anti-HIV-1 drugs selected from, NNRTIs and PIs. Typical suitable HAARTxe2x80x94multidrug combination therapies include:
(a) triple combination therapies such as two NRTIs and one PI; or (b) two NRTIs and one NNRTI ; and (c) quadruple combination therapies such as two NRTIs , one PI and a second PI or one NNRTI. In treatment of naive patients, it is preferred to start anti-HIV-1 treatment with the triple combination therapy; the use of two NRTls and one PI is preferred unless there is intolerance to PIs. Drug compliance is essential. The CD4+ and HIV-1-RNA plasma levels should be monitored every 3-6 months. Should viral load plateau, a fourth drug, e.g., one PI or one NNRTI could be added. See the table below wherein typical therapies are further described:
A. Triple Combination Therapies
1. Two NRTIs1+one PI2 
2. Two NRTIs1+one NNRTI3
B. Quadruple Combination Therapies4 
Two NRTIs+one PI+a second PI or one NNRTI
C. Alternatives:5 
Two NRTI1 
One NRTI5+one PI2 
Two PIs6xc2x1one NRTI7 or NNRTI3 
One PI2+one NRTI7+one NNRTI3 
Footnotes to Table
1. One of the following: zidovudine+lamivudine; zidovudine+didanosine; stavudine+lamivudine; stavudine+didanosine; zidovudine+zalcitabine
2. Indinavir, nelfinavir, ritonavir or saquinavir soft gel capsules.
3. Nevirapine or delavirdine.
4. See A-M. Vandamne et al Antiviral Chemistry and Chemotherapy 9:187 at p 193-197 and FIGS. 1+2.
5. Alternative regimens are for patients unable to take a recommended regimen because of compliance problems or toxicity, and for those who fail or relapse on a recommended regimen. Double nucleoside combinations may lead to HIV-resistance and clinical failure in many patients.
6. Most data obtained with saquinavir and ritonavir (each 400 mg bid).
7. Zidovudine, stavudine or didanosine.
Agents known in the treatment of rheumatoid arthritis, transplant and graft v. host disease, inflammatory bowel disease and multiple sclerosis which can be administered in combination with the CCR5 antagonists of the present invention are as follows:
solid organ transplant rejection and graft v. host disease: immune suppressants such as cyclosporine and Interleukin-10 (IL-10), tacrolimus, antilymphocyte globulin, OKT-3 antibody, and steroids;
inflammatory bowel disease: IL-10 (see US 5,368,854), steroids and azulfidine;
rheumatoid arthritis: methotrexate, azathioprine, cyclophosphamide, steroids and mycophenolate mofetil;
multiple sclerosis: interferon-beta, interferon-alpha, and steroids.
Certain compounds of the invention may exist in different isomeric forms (e.g., enantiomers, diastereoisomers, atropisomers and rotamers). The invention contemplates all such isomers both in pure form and in admixture, including racemic mixtures.
Certain compounds will be acidic in nature, e.g. those compounds which possess a carboxyl or phenolic hydroxyl group. These compounds may form pharmaceutically acceptable salts. Examples of such salts may include sodium, potassium, calcium, aluminum, gold and silver salts. Also contemplated are salts formed with pharmaceutically acceptable amines such as ammonia, alkyl amines, hydroxyalkylamines, N-methylglucamine and the like.
Certain basic compounds also form pharmaceutically acceptable salts, e.g., acid addition salts. For example, the pyrido-nitrogen atoms may form salts with strong acid, while compounds having basic substituents such as amino groups also form salts with weaker acids. Examples of suitable acids for salt formation are hydrochloric, sulfuric, phosphoric, acetic, citric, oxalic, malonic, salicylic, malic, fumaric, succinic, ascorbic, maleic, methanesulfonic and other mineral and carboxylic acids well known to those in the art. The salts are prepared by contacting the free base form with a sufficient amount of the desired acid to produce a salt in the conventional manner. The free base forms may be regenerated by treating the salt with a suitable dilute aqueous base solution such as dilute aqueous NaOH, potassium carbonate, ammonia and sodium bicarbonate. The free base forms differ from their respective salt forms somewhat in certain physical properties, such as solubility in polar solvents, but the acid and base salts are otherwise equivalent to their respective free base forms for purposes of the invention.
All such acid and base salts are intended to be pharmaceutically acceptable salts within the scope of the invention and all acid and base salts are considered equivalent to the free forms of the corresponding compounds for purposes of the invention.
Compounds of the invention can be made by the procedures known in the art, for example by the procedures described in the following reaction schemes, by the methods described in the examples below, and by using the methods described in WO96/26196 and WO98/05292.
The following solvents and reagents may be referred to herein by the abbreviations indicated: tetrahydrofuran (THF); ethanol (EtOH); methanol (MeOH); acetic acid (HOAc or AcOH); ethyl acetate (EtOAc); N,N-dimethylformamide (DMF); trifluoroacetic acid (TFA); 1-hydroxy-benzotriazole (HOBT); m-chloroperbenzoic acid (MCPBA); triethylamine (Et3N); diethyl ether (Et2O); dimethylsulfoxide (DMSO); and 1-(3-dimethylaminopropyl)-3-ethyl carbodiimide hydrochloride (DEC). RT is room temperature, and TLC is thin-layer chromatography. Me is methyl, Et is ethyl, Pr is propyl, Bu is butyl, Ph is phenyl, and Ac is acetyl. 
Reagents and conditions: a: R4CH(OSO2CF3)CO2CH3, base (e.g., K2CO3); b: ClCH2COCl; c: NH3; d: NaBH4-BF3; e: N-Boc-4-piperidone, NaBH(OAc)3; f: CF3CO2H; g: acylation; h: N-Boc-4-piperidone, Ti(OPr-i)4, Et2AlCN; i: CH3MgBr.
In Scheme 1, a benzylamine (1), wherein R and R3 are as defined above and R1 is hydrogen, is converted via (2) and (3) to the diketopiperazine (4), wherein R4 is as defined above, which is reduced to the piperazine (5). Depending upon the desired R6 substituent, this is processed in two ways. Reductive amination gives (6), which can be deprotected to (7) and finally acylated to the compounds of formula IA wherein R5 and R6 are H; alternatively, a modified Strecker reaction on (5) gives the aminonitrile (8), which, after treatment with methyl Grignard to give (9), deprotection to (10) and final N-acylation affords the compounds of formula IB wherein R5 is H and R6 is methyl. Acylation of (7) and (10) is carried out under standard conditions, e.g., with a compound R2COOH and reagents such as DEC and HOBT. Use of a chiral compound of formula 1, e.g., (S)-methyl 4-substituted benzylamine, and a chiral lactate in step a, e.g., methyl (R)-lactate triflate, will result in chiral compounds of formulas IA and IB. 
Reagents: j: oxaborazolidine, BH3; k: CH3SO2Cl, base; I: CF3CO2H.
In Scheme 2, the compounds are prepared by an alkylation process on a pre-formed piperazine derivative. For example, preferred compounds with the S,S stereochemistry may be obtained in this way by chiral reduction of a ketone (11) to the alcohol (12), activation as the mesylate, and displacement with inversion by treatment with a suitable piperazine, which may either be mono-protected, in which case final elaboration requires deprotection followed by the steps described in (e)-(g) in Scheme 1 to obtain IC, or may be elaborated prior to the displacement step, in which case the final steps are (1) and (g) (deprotection and acylation) as in Scheme 1 to obtain ID. 
For compounds where R3 and R1 are each H, either the alkylation route of Scheme 2 or a reductive amination method as typified in Scheme 3 can be used. 
For diaryl compounds, wherein R and R3 are each aryl, an alkylation method as typified in Scheme 4 is preferrred. 
Piperazines of formula 14, especially those wherein R3 is C2-C6 alkyl or benzyl, may also be obtained by a process wherein the 
portion is introduced as shown above by an alkylation-decyanation sequence. The reaction is exemplified for compounds wherein R is CF3O-phenyl, R1 is hydrogen, R3 is ethyl and R4 is methyl, but using appropriate starting materials, other compounds of formula 14 can be similarly prepared. 
Reagents: m: BOC2O, base; n: R6MgBr; o: CCl3CO2H, NaBH3CN; p: CF3CO2H; q: NaBH4, BF3.
As shown in Scheme 6, compounds bearing an additional alkyl group at R5 on the piperazine ring may be prepared from the diketopiperazine intermediates (4) of Scheme 1. (4) is activated by conversion to the N(t-butoxycarbonyl) compound (17); addition of a Grignard reagent and sequential reduction, deprotection and lactam reduction provides (21), which can be used to prepare compounds of formula I in the manner described for intermediate (5) in Scheme 1. 
Many piperazines wherein R is R8-phenyl (or their Boc derivatives) shown in Scheme 1 can be obtained from a common intermediate, wherein R8 is I. Several examples are shown in the above scheme, wherein R8 is converted to Cl, CN, xe2x80x94C(O)NH2, H, Ph and p-ClC6H4CH2-. Detailed procedures for these conversions are provided in the examples below. The resultant piperazine or BOC-piperazine is then treated as shown in Scheme 1. 
Some compounds of the invention may be obtained by a Mannich method, as shown in the specific example of Scheme 8.
Compounds useful in this invention are exemplified by the following preparative examples, which should not be construed to limit the scope of the disclosure. Alternative mechanistic pathways and analogous structures within the scope of the invention may be apparent to those skilled in the art.